Known metabolic products of microorganisms include a variety of organic compounds having different chemical structures and different physiological activities. The techniques which use the known metabolic products of microorganisms as antibiotics have been extensively investigated and utilized. We, the present inventors, have investigated physiological activities of these metabolic products having special chemical structure, in respect of their activities other than the antibacterial and antifungal properties so as to use the metabolic products of microorganisms as medical drugs other than the antibiotics. In the course of the series of our investigations, actinonin--the compound which had been described as an antibiotic having antibacterial activity in literature (for example, U.S. Pat. No. 3,240,787 Specification) and which is represented by the formula (II) ##STR2## --was found to inhibit a wide variety of peptidases [see "Journal of Antibiotics", 38, 1629-1630 (1985)].
Besides, we discovered that actinonin has an immunopotentiating activity (see Japanese patennt application first publication "Kokai" No. 15840/86 or U.S. Pat. No. 4,663,342) and that actinonin can inhibit the enkephalin-degrading enzymes and shows an anodyne activity (see Japanese patent application first publication "Kokai" No. 4228/87).
The previous syntheses of related compounds of actinonin have also been investigated for the limited purpose to improve the antibacterial activities of actinonin and are reported in the literature "Journal of the Chemical Society, Perkin Transactions I", 1975, page 846.
When actinonin is intentionally used as an enzyme-inhibitor against such enzymes which are produced by mammals including man, the inherent antibacterial activities of actinonin do not contribute to the enzyme-inhibitory effects of actinonin to be utilized and rather are an undesired property.
While, the previous investigations made for the purpose to synthetize the actinonin-related compounds have each been performed by a total synthetic process and hence have not provided industrial processes of preparing the actinonin-related compounds. According to an investigation made by the present inventors, it has been noted that the enzyme-inhibitory effects of actinonin are lacking the enzyme-specificity. Actinonin can therefore inhibit a wide range of enzymes and accordingly, has a problem that actinonin is not suitable for use as a medical drug for human.
We, the present inventors, have been proceeding with our investigations with a view toward producing such novel actinonin-related compounds, which are useful as a peptidase-inhibitor having a high enzyme-specificity, by using a fermentatively produced actinonin as a starting material for synthesis of actinonin-related compounds, and then effecting chemical modifications of actinonin. We have expected that the unsuitability of actinonin as a medical drug can be solved if we have succeeded in synthetizing such new actinonin-related compounds which are useful as a peptidase-inhibitor with a high enzyme-specificity. As stated hereinbefore, actinonin can exhibit the antibacterial activities and inhibit a wide range of substrates and a broad range of peptidases. For instance, actinonin shows a medium enzyme-inhibitory activities against two kinds of enzymes, namely, angiotensin-conversion enzymes (abbreviated as "ACE") and the above-described enzyme PPCE. We have now found that the removal of the hydroxyamino group present in the actinonin molecule which is essential for the development of the antibacterial activity of actinonin can provide a class of novel actinonin-related compounds which are represented by the general formula (I) given below and can inhibit only certain limited kinds of peptidases.
As a result of our investigations, we have now succeeded in synthetizing and providing a class of new actinonin-related compounds which are represented by the general formula (I) given below and which are inhibitory to the limited range of peptidases and are of a high enzyme-specificity.